Thomas Castles

Despite many advancements made in the fight against HIV, there are still many unknowns. One question of interest to many investigators is, how does HIV affect the brain? It is uncertain if the virus is directly associated with neurocognitive decline; however, there is substantial evidence that suggests that virus indirectly manifests in poorer neurocognitive outcomes.

 in San Diego, California, Shibani Mukerji, MD, PhD, of the Department of Neurology at Massachusetts General Hospital, shared that very early on in infection, the virus invades the central nervous system (CNS).

“Within days of plasma viremia, HIV RNA can be detected in the cerebrospinal fluid [CSF], and this early penetration is hypothesized to set the stage for future neurocognitive impairment,” Dr. Mukerji said.

The CNS has its own unique immune surveillance, Dr. Mukerji explained, however, recent studies indicate that this immune surveillance is complemented by input from the peripheral immune system. Peripheral cells, including t-lymphocytes, enter the CNS under normal conditions, but during HIV infection and immune activation, there is a heightened trafficking of these cells, which can harbor HIV.

“When an HIV infected cell enters the brain, there is a release of inflammatory cytokines and chemokines, which then attract more immune cells. There is a cycle of inflammation that is established,” Dr. Mukerji explained.

studies suggest that these inflammatory processes, and perhaps toxic effects from viral proteins, will eventually damage neurons, driving brain atrophy and neurocognitive impairment. According to Dr. Mukerji, this neurocognitive decline is not due to direct viral infection, but bystandards for these local inflammatory processes.

In primary HIV infection, CSF inflammatory markers are elevated. Dr. Mukerji explained that this correlates with systematically low CD4 cell counts, which has been associated with worse neurocognitive outcomes, even when excluding opportunistic infections.

Dr. Mukerji cited a recent study conducted at UCSF to illustrate this point. In the study, researchers monitored the first 20 days of estimated exposure to HIV and identified that there is already increased activated CDAT cells present in the CSF at the time of peak viremia; this is carried over into chronic HIV.

“What’s slightly concerning to me is that in this acute phase, we are already seeing differences in brain volume and structural brain MRI,” Dr. Mukerji admitted.

The MRI study calculated the volume of a brain tissue and showed that within a very small number of days after estimated infection, and prior to antiretroviral initiation, volumes were getting smaller.

“What this really suggests is that within weeks of estimated infection, HIV may already be altering the underlying neural anatomy of our brains and altering our neural networks,” Dr. Mukerji said.

While HIV may play a role in exacerbating neurocognitive impairment, similarly, neurocognitive impairment can result in poorer HIV outcomes.

“Neurocognitive disorders affect antiretroviral adherence and viremia, and can affect work, financial considerations, and impact overall quality of life,” Dr. Mukerji said.

Twenty percent of new HIV diagnoses in 2015 were in individuals over the age of 50, and 40% of those individuals had a late-stage infection at the time of their diagnosis. Odds of neurocognitive impairment increased by 20% with every decade of life.

Earlier diagnosis is key to treating these patients and helping them achieve better HIV and neurocognitive outcomes. However, despite ART, it is known that neuroinflammation is established in acute HIV infection that persists into chronic infection. 

“There are decrease in some, but not all CSF cytokine markers [with earlier ART initiation], and interestingly they did show that viral diversity in the CSF increased the longer it took to start ART,” Dr. Mukerji said. “We’re getting new data suggesting that maybe earlier treatment for ART may improve some cognitive markers, but I think that needs to be tested out a little bit more.”

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Dr. Shibani Mukerji discusses how HIV affects the brain as part of a symposium at ID Week 2017.

How Does HIV Affect the Brain?

Those with chronic hepatitis C virus (HCV) genotypes 1-6 (with mild cirrhosis or without cirrhosis) now have a new treatment option. The US Food and Drug Administration (FDA) just approved a new treatment option: Gilead Sciences’ 

The Centers for Disease Control and Prevention (CDC) estimates that a staggering 2.7 to 3.9 million individuals in the United States suffer from chronic HCV. With new infections occurring every day—particularly in light of the 

—a new treatment option is particularly welcome.

Vosevi is a combination of 2 previously approved drugs—sofosbuvir and velpatasvir&mdash;plus a new drug called voxilaprevir. It is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir, or other drugs for HCV that inhibit NS5A proteins, the FDA said in a 

The drug was given priority review, which is granted to drugs that, if approved, would markedly improve the safety or efficacy of a treatment of a serious condition. It was also given breakthrough therapy status, which is granted to drugs that could demonstrate a substantial improvement over available therapies.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research commented in the statement.

Vosevi’s safety and efficacy were evaluated in two phase 3 clinical trials that enrolled around 750 adults with mild cirrhosis or without cirrhosis at all.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5, or 6 all received Vosevi. The second trial compared 12 weeks of Vosevi treatment with the previously approved drugs that comprise two thirds of Vosevi’s makeup — sofosbuvir and velpatasvir – in adults with genotypes 1, 2 or 4 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

In both trials, the majority of patients (96% to 97%) who took Vosevi had no detectable virus in their blood 12 weeks after finishing treatment, suggesting that the patients’ infection had been cured.

Vosevi is contraindicated for patients taking the drug rifampin. The most common adverse reactions were headache, fatigue, diarrhea and nausea.

The FDA has approved Gilead Sciences’ Vosevi for the treatment of adults with chronic hepatitis C virus genotypes 1-6, without cirrhosis or with mild cirrhosis.

FDA Approves Vosevi to Treat Those Infected with Chronic Hepatitis C

The National Institutes of Health (NIH) is looking to determine whether Zika virus infection poses an additional risk in women whose pregnancies are already complicated by HIV. Specifically, NIH researchers are concerned that Zika may have the potential to interfere with medications that prevent HIV from being passed from a pregnant woman to her fetus, and therefore, increase the chance of the fetus becoming infected. Similar effects have been seen in women with coinfections with syphilis and type 2 herpes simplex virus.

“Other studies have shown that the presence of a co-infection can influence mother-to-child HIV transmission,” said the study’s lead author Catherine Spong, MD, in an interview with 

. “So we’re looking to this study to provide similar information on whether co-infection with HIV and the Zika virus affects the transmissibility of either one or both of these viruses.

 aims to uncover any previously unidentified connection between the conditions, and whether the effects of either disease are exacerbated by the other.

“We know very little about how co-infection with HIV and Zika could affect women, pregnancy and infants. Given that Zika infection rates are likely to increase in many parts of the world where HIV infection is widespread, we hope to uncover information that will help practitioners provide the best care for their patients,” Dr. Spong said.

A total of 200 pregnant women will be initially enrolled in the study. The study group will include:

pregnant women who are infected with HIV only,

pregnant women infected with Zika virus only,

pregnant women infected with HIV and Zika virus,

and women not infected with either virus. 

If successful, the researchers will attempt to enroll an additional 1800 pregnant women, for a total study group of 2000. All women in the study will be monitored throughout their pregnancies and for 6 months after giving birth. Infants will be observed for 1 year after birth. The study is expected to fun from 4 to 6 years.

“Given the neurotoxic effects seen in newborns of mothers with Zika infection, we’re especially interested in determining whether co-infection influences the rate of neurological complications,” Dr. Spong told 

. “In addition, there has been a question on whether coinfection, such as with Dengue or other flaviviruses, potentiates the impact of Zika virus. This study will be able to add to that information by studying the impact of HIV on Zika.”

The study is currently enrolling participants in Puerto Rico. Recruitment will soon begin at sites in the continental United States and in Brazil.

This is not the only NIH-led Zika virus-related study. In June 2017, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) announced that they are teaming up with FUNSALUD, a non-profit organization, to conduct a large natural history study that will take a closer look at neurologic, neurodevelopmental, and 

clinical outcomes pertaining to Zika virus in infants

 and young children residing in Guatemala. The researchers of the study hope that the findings yielded from this research will not only “help inform global public health practices and assist Guatemalan health officials as they seek to understand the risks associated with early childhood Zika infection,” but also help create “healthcare programs that will provide Zika-related healthcare of benefit to Guatemalan children and families.”

The National Institutes of Health (NIH) is looking to determine whether Zika virus infection poses an additional risk in women whose pregnancies are already complicated by HIV.

Thomas Castles

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